Stent for keeping open tubular structures

ABSTRACT

A stent made of metallic and/or non-metallic material that can be implanted into tubular structures or other body cavities is coated with nanoscale particles that consist of a paramagnetic core and at least one shell adsorbed to it which is durably bonded to the stent surface. This coating makes it possible to selectively and homogeneously heat up the implant by applying an alternating magnetic field with a clinically tolerable combination of field strength and frequency, thereby achieving high power absorption and, on the one hand, a temperature level that enhances the growing-in of the implant by enhancing cell proliferation, on the other hand, a temperature range in which a restenosed implant can be regenerated. Also, it facilitates position detection.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a stent for keeping open tubular structures inthe human body and to prevent restenosis by action eat.

2. Brief Description of the Prior Art

When treating the occurrence of stenoses in tubular structures such asvessels, the urinary tract and the like, or vascular aneurysms, stentsor intraluminal tubes, i.e. generally tube-shaped supports made of metaland/or a polymer are implanted into the respective hollow viscus to keepthe contracted structures open. The problem of using such implants is,however, that restenosis or an obstruction occurs soon afterimplantation, requiring another highly risky and costly surgicaloperation. When restenosis of cardiovascular stents occurs, an extensivebypass operation quite frequently is the only option.

Special catheters and microtools or laser tools are typically used tomechanically lay open the obstructive area of the stent underangiographic monitoring. Such regeneration, however, can be done twiceat best. After that the stent support has to be replaced by a newimplant.

Use of radioactive stents has been proposed to prevent the disadvantagesmentioned above (U.S. Pat. No. 5,840,009, as re-embedding of endotheliaor smooth muscle cells within the stent would not occur in the nearrange of radiation. However, exact dosage of radiation is difficult, andits cytotoxic effects are still uncertain.

Furthermore, stents have been described that are coated withanti-adhesion molecules (DE 197 13 240), fibrin/fibrinogen (U.S. Pat.No. 5,660,873), silicone (U.S. Pat. No. 5,330,500), or carbon (U.S. Pat.No. 5,163,958) or that come with a therapeutic delivery system (U.S.Pat. No. 5,439,446) to prevent restenosis.

Also known are stents made of a heat recoverable material (U.S. Pat. No.5,197,978) that are connected to an electric heater, are introduced intoa stenosed area of a hollow viscus and thermally dilated using a ballooncatheter and can later be recovered to their original configuration.Finally publications (U.S. Pat. No. 5,178,618) describe expandablestents that can be heated to temperatures between 50° C. and 100° C.using external radiofrequency waves for ducting and stenosing tubularstructures in the human body. Generation of heat in the stent materialprevents proliferation of smooth muscle cells which are assumed to beresponsible for restenosis of the stent and the resulting adverseconsequences described at the outset.

Regeneration of electroconductive iron-containing restenosed stents inthe body faces the setback that they only heat up at a relatively highfield strength-frequency combination due to hysteresis and eddy-currentlosses that result in power absorption in the electroconductive tissueat the body surface and thus undesirable overheating of the peripheraladipose tissue and other uninvolved tissue. Regenerating metallic andnon-metallic implants using heat has thus been unfeasible.

SUMMARY OF THE INVENTION

It is therefore the problem of this invention to provide a stent of theabove type that, both in its metallic and non-metallic designs, can beselectively heated as desired to prevent restenosis or obstruction andto facilitate the stent's growing into the respective hollow viscus.

This problem is solved according to the invention by providing a stentconsisting of a metallic and/or non-metallic material and coated withnanoscale particles that comprise a paramagnetic core and a coveringthat can adsorb to the stent for position detection by MR tomography andfor homogeneous and controlled heating and power absorption in analternating magnetic field with a specific field strength and frequencysuitable for clinical use.

The stent implant according to the invention, in metallic ornon-metallic design, to the surface of which nanoscale particles arebonded in an even distribution pattern, makes it possible to set acontrollable temperature that is restricted to the stent and slightlyabove the normal physiological temperature in a field strength andfrequency range suitable for clinical use, thereby ensuring fastgrowing-in of the implant through enhancing the proliferation of newcells and regeneration of the restenosed stent at a temperature rangefrom 50 to 60° C. Due to their coating with nanoscale particles, bothmetallic and non-metallic designs of the implants are capable of highpower absorption at field strengths below 10 kA/m and in a frequencyrange suitable for clinical use. Also, the stents heat up evenly. Inaddition, the provided coating allows position detection of the stentusing MR tomography, no matter which implant material is used.

In a further improvement of the invention, said nanoscale particlesconsist of a core that contains, preferably consists of, ferromagnetic,ferrimagnetic, or preferably supramagnetic iron oxide and a coveringmade of at least one shell-adsorbing to the core. Said shell(s)comprise(s) reactive groups that can form cationic groups for permanentbonding of the outer shell to the surface of the stent. Said nanoscaleparticles are produced using known methods, such as the methodsdescribed in German laid-open patent publications nos. 195 15 820, 19614 136, and 197 26 282.

DETAILED DESCRIPTION OF THE INVENTION

More specifically, the invention is a stent for keeping open tubularstructures and restenosis prevention by heating said stent. The stentincludes a tube-shaped support made of a metallic and/or non-metallicmaterial coated with nanoscale particles each of which includes aparamagnetic core and a covering that can adhere to said stent forposition detection by MR tomography and for homogeneous and controlledheating and power absorption in an alternating magnetic field having aspecific field strength and frequency suitable for clinical use.

Each nanoscale particle includes a ferromagnetic, ferrimagnetic orsupramagnetic core and at least one shell surrounding said core that canabsorb to said core. The shell comprises reactive groups capable offorming cationic groups that are degraded so slowly by body tissue thatthe outer shell durably bonds to the surface of said stent made ofmetallic and/or non-metallic material.

The core of each nanoscale particle can consist of (1) pure iron oxidethat includes magnetite and/or maghemite; (2) pure Fe (II): Fe (III)iron particles at ratios from 1:1 to 1:3; or (3) iron containing mixedoxides having a content of non-ferrous metallic atoms desirably notgreater than 70% and more desirably not greater than 35% of metallicatoms.

The reactive groups can include monomeric aminosilanes and carboxylgroups. The shell can absorb to the stent through microemulsion ortenside-mediated reactions.

The covering on each nanoscale particle can further include another,outer shell of nanoscale particles for attachment of biomolecules. Thebiomolecules can be one of fibrinolytic or anti-coagulant enzymes suchas protease, heparin or a heparin derivative. The average diameter ofthe nanoscale particles is desirably smaller than 100 nm, more desirablysmaller than 50 nm and most desirably smaller than 30 nm. The averageparticle size is desirably between 1 and 40 nm and, more desirablybetween 3 and 30 nm.

The stent can be configured to be heated up in an alternating magneticfield for producing rapid gradient fields within NMR tomography.

In a test arrangement, the fibrinogen portion of a fibrin-fibrinogensolution was thoroughly mixed with 15 mg/ml of a preparation ofnanoscale particles coated with aminosilane. A commercially availableendovascular stent of an expandable metallic design was then dipped intothe fibrin-fibrinogen solution prepared as described above. The coatingof nanoscale particles obtained in this way remained stable on the wirefabric of the stent when it was subsequently dilated using a ballooncatheter. The coated stent was inserted into a tube filled with waterand exposed to an alternating magnetic field with a strength of 10 to 18kA/m and at a frequency of 100 kHz. An uncoated stent was also exposedto the alternating field for comparison. It was found that the coatedstent absorbs sufficient power and heats up as required for regenerationof restenosed stents at a field strength of just 10 kA/m. The uncoatedstent, however, is not heated up in this clinically relevant fieldstrength range in which no undesired heating up of other tissue occurs.The uncoated stent reaches a sufficiently high power absorption and theassociated heating up of the stent and other tissues at field strengthsof 15 kA/m and more. This means that power absorption of the stentcoated with nanoscale particles at 10 kA/m matches that of the uncoatedstent at 15 kA/m.

Based on the power absorption (W/g) calculated as a function of fieldstrength and frequency and the perfusion rate in the vessel or hollowviscus in which the stent is implanted, the temperature-time curve ofheating up the stent in the human body by applying an alternatingmagnetic field at a specific frequency can be calculated. In practicaluse, a fiber-optic temperature-measuring probe is inserted into thestent via a stent implantation catheter and monitored by angiography sothat the temperature is checked while said alternating magnetic field isapplied. The implanted stent is heated to a temperature slightly abovethe normal physiological level to accelerate its growing-in bystimulating cell growth on the surface of the implant. If the stentimplant has to be regenerated later due to restenosing, perfusion in thestent area is determined prior to applying the alternating magneticfield. The exact position of the implant can be determined by contrastmedia radiography or NMR tomography.

I claim:
 1. A stent for keeping open tubular structures and restenosisprevention by heating, said stent comprising a tube-shaped support madeof one of a metallic and a non-metallic material coated with nanoscaleparticles, with each nanoscale particle including a paramagnetic coreand at least one shell that adheres to said stent for position detectionby MR tomography and for homogeneous and controlled heating and powerabsorption in an alternating magnetic field with a specific fieldstrength and frequency suitable for clinical use, wherein: eachnanoscale particle consists of one of a ferromagnetic, ferrimagnetic andsupramagnetic core; said shell surrounds and adsorbs to said core; andsaid shell comprises reactive groups formed from monomeric aminosilanescapable of forming cationic groups that are degraded so slowly by bodytissue that said shell durably bonds to said stent when said stent is incontact with the body tissue.
 2. The stent according to claim 1, whereinthe core of each nanoscale particle consists of pure iron oxide thatincludes at least one of magnetite and maghemite.
 3. The stent accordingto claim 1, wherein the core of each nanoscale particle consists of pureFe (II):Fe (III) iron oxide particles at ratios from 1:1 to 1:3.
 4. Thestent according to claim 1, wherein the core of each nanoscale particleconsists of iron-containing mixed oxides having a content of non-ferrousmetallic atoms not greater than 70% of metallic atoms.
 5. The stentaccording to claim 1, further including another shell of said nanoscaleparticles for attachment of biomolecules.
 6. The stent according toclaim 5, wherein the biomolecules arc one of fibrinolytic andanti-coagulant enzymes.
 7. The stent according to claim 6, wherein theone of the fibrinolytic and anti-coagulent enzymes are one of aprotease, heparin and a heparin derivative.
 8. The stent according toclaim 1, wherein the average diameter of each nanoscale particle issmaller than 100 nm.
 9. The stent according to claim 8, wherein theaverage diameter of each nanoscale particle is between 1 nm and 40 nm.10. The stent according to claim 9, wherein the average diameter of eachnanoscale particle is between 3 nm and 30 nm.
 11. The stent according toclaim 8, wherein the stent is designed to be heated up by an alternatingmagnetic field for producing rapid gradient fields within NMRtomography.
 12. The stent according to claim 8, wherein the averagediameter of each nanoscale particle is smaller than 50 nm.
 13. The stentaccording to claim 8, wherein the average diameter of each nanoscaleparticle is smaller than 30 nm.
 14. The stent according to claim 13,wherein the core of each nanoscale particle consists of iron-containingmixed oxides having a content of non-ferrous metallic atoms not greaterthan 35% of metallic ions.